11.Title: “Genome-wide association study of multisite chronic pain in UK Biobank (2019).”
11.1 Abstract
Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP.
11.2 Author summary
In this study we searched for genetic variants associated with chronic pain in a large general-population cohort.
11.3 Introduction
Several aspects of chronic pain, such as chronic pain grade and back pain, have been studied from the genetic point of view, and several have been shown to be complex traits with moderate heritability. In part due to the heterogeneity of pain assessment and pain experience, there are very few large-scale genetic studies of chronic pain and no genome-wide significant genetic variants have yet been identified.
Chronic pain and chronic pain disorders are often comorbid with psychiatric and neurodevelopmental disorders, including Major Depressive Disorder (MDD). The immune and nervous systems play a central role in chronic pain development and maintenance. Chronic pain is also a common component of many neurological diseases. Structural and functional changes in the brain and spinal cord are associated with the development and maintenance of chronic pain, and affective brain regions are involved in chronic pain perception (this is in contrast to acute pain and even to prolonged acute pain experience).
11.4 Discussion
We identified 76 independent genome-wide significant SNPs associated with MCP across 39 loci. The genes of interest had diverse functions, but many were implicated in nervous-system development, neural connectivity and neurogenesis.
12.Title: “Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain (2021).”
12.1 Abstract
Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types.
12.2 Introduction
The dorsal root ganglion (DRG) consists of a variety of neuron types, each tuned to detect and transduce different physical stimuli. These neuron types can broadly be divided into low-threshold mechanosensitive neurons responsible for sensing touch and high-threshold nociceptors, which are involved in pain, temperature, and itch. However, a comprehensive classification of DRG neurons is critical for understanding exactly how somatosensation works and for providing insights into the cellular basis for acute and chronic pain.
This has enabled the identification of molecular types representing richly myelinated A-fiber low-threshold mechanoreceptors (LTMRs) and limb proprioceptors. The remaining neuronal types in the scRNA-seq are assigned as weakly myelinated or unmyelinated neurons. One of these is a C-fiber LTMR (C-LTMR) neuron type that expresses Vglut3 (Slc17a8) and tyrosine hydroxylase (Th) that likely is not involved in pain sensation. Nociception is largely conferred through unmyelinated peptidergic C-fiber neuron types and a few lightly myelinated Aδ-nociceptors, a Trpm8 expressing cluster of neurons, as well as cell types marked by expression of Mrgprd, Mrgpra3, or Sst (named NP1, NP2, and NP3 types of neurons, respectively).
Hence, the concordance of markers used in different studies and their relation to actual neuron types remain largely unknown. Nevertheless, by examining individual gene products, these studies suggest important species differences between human and mouse where, for example, Nav1.8, Nav1.9, P2X3 receptor, and TRPV1 are present in both small and large neurons in humans, but only small neurons in mouse, suggesting fundamental differences in molecular characteristics and principles of initiation and transduction of somatosensory stimuli between humans and rodent.
In humans, rare and drastic mutations that explain different types of congenital insensitivity to pain and erythromelalgia have been identified, such as, for example, SCN9A (Nav1.7), NTRK1 (TRKA), and SCN11A (Nav1.9). In addition to these rare causing mutations, it is known that the genetic risk for chronic pain is due to common variations with small effect size. Close to half of the risk of developing chronic pain are attributable to genetic factors, including musculoskeletal pain conditions. For musculoskeletal pain there is statistical evidence for a diverse set of genes involved, with a marked overrepresentation of genes expressed in neurons and functionally associated with neurotransmission, indicating a strong heritable component caused by altered functions of neurons. Pleiotropy of single-nucleotide polymorphisms (SNPs) among painful and non-painful conditions has also been shown, even in human DRG.
We conclude that the mouse and the Rhesus macaque largely share molecular neuron types which using mouse genetics have been functionally identified as A-LTMRs involved in touch and proprioceptive sensation, C-LTMRs involved in the affective aspect of pleasant touch, C-cold thermoreceptors (TrpM8high), Aδ fast mechanical nociceptors involved in pinprick pain (PEP2) and mechano-heat C-nociceptors (PEP1), as well as “non-peptidergic” neuronal types (NP1, NP2, NP3) known in mouse to be involved sensing noxious mechanical threshold and itch sensation.
13.Title: “Nociception (2017).”
Tracey, W. D., Jr. (2017). “Nociception.” Curr Biol 27(4): R129-R133.
13.1 Summary
Nociception, the sensory mechanism that allows animals to sense and avoid potentially tissue-damaging stimuli, is critical for survival. This process relies on nociceptors, which are specialized neurons that detect and respond to potentially damaging forms of energy — heat, mechanical and chemical — in the environment. Nociceptors accomplish this task through the expression of molecules that function to detect and signal the presence of potential harm. Downstream of the nociceptive sensory input, the neural signals trigger protective (nocifensive) behaviors, and the sensory stimuli that reach the brain may be perceived as painful.
13.2 Nociceptors and the stimuli they detect
Nociceptors may be polymodal and activated by several classes of noxious stimulus (i.e. heat, mechanical and chemical stimuli), or they may be more specialized in their responses. The cell bodies of the mammalian nociceptor neurons are found in the peripheral nervous system in dorsal root and trigeminal ganglia. Axons from the nociceptive neurons output to neural circuits in the dorsal horn of the spinal cord, which in turn transmit the inputs to the brain through ascending neuronal pathways. It is in the brain where pain perception occurs downstream of the nociceptive input. Nociception and pain are thus separable processes: pain can occur in the absence of nociceptive input and nociception can occur in the absence of pain.
When the signals from the periphery reach the brain, the quality of the painful sensation is related to the type of neuron that has been activated. With noxious heat stimuli the intensity of the pain correlates with the strength of activation of slowly conducting unmyelinated C-fibers that rapidly adapt to the heat stimulus, but with prolonged heat stimuli heat pain is also carried by rapidly conducting thinly myelinated axons (A-δ fibers) that show more prolonged and non-adapting responses. Both the A-fibers and the C-fibers can also be mechanically sensitive and are involved in the transmission of mechanical pain. Many fibers are polymodal and can be activated by both high threshold mechanical and thermal stimuli.
13.3 Sensitization, hyperalgesia, and efferent function of nociceptors
The nociceptive terminals of C-fibers in the skin have vesicles containing neuropeptides such as substance P and calcitonin gene related peptide that are released upon stimulation to cause physiological effects in the surrounding tissue. The combined effects produce so-called ‘neuroinflammation’. The well-known redness and swelling or ‘flare’ that can be seen in the skin surrounding a localized heat or mechanical injury is the result of neuroinflammatory effects on the local vasculature. Swelling is due to local release of blood plasma (plasma extravasation) and redness is due to local vasodilation, which provides increased blood flow to the site of injury. The flare that occurs following nociceptor activation covers a significantly larger area than the site of the stimulus itself and is likely due to a peripheral axon reflex where the action potentials of the stimulus spread into adjacent branches of the nociceptor neuron.
Following injury the nociceptors themselves may become sensitized by the release of proinflammatory mediators, such as prostaglandins, bradykinin, substance P, extracellular ATP and protons. With sensitization, nociceptors can become activated by normally innocuous stimuli (a process known as allodynia) and activated even more strongly by painful stimuli (a process known as hyperalgesia).
13.4 Molecular mechanisms of nociception
In order for nociceptive neurons to transmit the presence of harmful energy to the central nervous system, molecules present in the nerve endings must detect these stimuli. The process by which harmful energy is converted into ionic currents is known as sensory transduction. Conduction occurs downstream of transduction, in the form of action potentials that are carried by the nerve fibers, and results in the release of neurotransmitters in the dorsal horn.
13.5 Thermal nociception
In mammalian nociceptors, noxious heat of more than 40oC activates the heat-sensitive C-fibers and heat of more than 52oC activates A-fibers. A great deal of excitement in the nociception field came with the discovery that members of the TRP family of ion channels could be activated by heating, with thresholds that were very well matched to the sensory thresholds of these fibers. This was first demonstrated with the discovery of TRPV1, the long sought-after receptor for capsaicin (the spicy ingredient of chili peppers): not only could the TRPV1 channel be activated by capsaicin, but it could also be directly activated by heat in the noxious range. This observation provided a potential molecular explanation for how thermal nociceptors could be activated by both noxious heat and by capsaicin (which is why chili peppers elicit a sensation of burning pain). Additionally, other mammalian TRP channels have been found to be activated by temperatures in the noxious range (i.e. TRPV2, TRPV3 and TRPV4).
13.6 Mechanical nociception
Relative to our understanding of the molecular mechanisms for the detection of noxious heat in mammals very little is known of the mechanisms for detection of noxious force. By analogy to other mechanosensory systems, the working hypothesis in the field is that mechanical nociception requires the action of force-sensing ion channels.
13.7 Chemical nociception
The general function of nociceptors in protecting organisms from tissue damage includes the ability of these sensory neurons to detect potentially damaging chemicals. The ability of nociceptors to detect a variety of seemingly unrelated chemical compounds was mysterious, until it was discovered that the nociceptor-specific ion channel TRPA1 could be activated by many of these chemicals. Although TRPA1 is not activated by the chili oils that activate TRPV1 (discussed above), it is activated by many other plant-derived and synthetic pungent chemicals. For instance, TRPA1 is activated by isothiocyanate compounds that represent the active ingredient of mustard oils found in Japanese horseradish (wasabi).
